Age-related maculopathy (ARM) is the leading cause of irreversible blindness in the elderly population and heredity is clearly the most important risk factor. Treatment for this group of conditions is extremely limited and primarily focused on minimizing the further loss of vision in patients with advanced disease. The long range objective of this project is to identify the genetic contributions to age-related maculopathy (ARM). The goal is to better understand the causes of this condition so that eventually preventive therapies can be developed and tested in at-risk individuals. We have established a rigorous diagnosis scheme for ARM, screened a series of 12 candidate loci, completed two autosomal 10 cM genome-wide scans on a total of 400 ARM families, and, by the end of the current funding period, will have completed a third 10 cM genome-wide scan on an additional set of 200 ARM families. We have one of the largest datasets of ARM families in the world for molecular genetic studies. While we are preparing to undertake our final genome-wide scan of ARM families with CIDR, we are initiating the investigation of the six regions of potential linkage that we have already identified. We will collect additional ARM families, as well as sporadic ARM cases and matched controls (from spouses) for additional testing using linkage and association methods. Microsatellite genotyping of ARM families will be done to further refine potential regions of interest. We will then use single nucleotide polymorphisms (SNPs) and association methods to study the two most promising regions that contain genes involved in ARM. From these studies, we can then proceed to evaluated individual candidate genes for their potential role in this condition. We will also use our large set of ARM subjects, families and controls to test candidate genes that are tentatively identified from other research studies.